Targeting EGFL6 in Ovarian Cancer

靶向 EGFL6 治疗卵巢癌

• 批准号: 10709231
• 负责人: ANIL K SOOD
• 金额: $ 30.66万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-19 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10709231
• 关键词: Adult; Adverse event; Affect; Aftercare; Angiogenesis Inhibitors; Antibodies; Area; Biological; Biopsy; Blood Vessels; CD4 Positive T Lymphocytes; CD8B1 gene; Cancer Model; Clinical; Collection; Complex; Computer software; Data; Data Analyses; Development; Endothelial Cells; Epidermal Growth Factor; Epithelial ovarian cancer; FDA approved; Fibroblasts; Genes; Genetic Transcription; Genomics; Growth; Home; Human; Hypoxia; Immune; Immune checkpoint inhibitor; Immune response; Immunosuppression; Infiltration; Interferons; Macrophage; Malignant Neoplasms; Malignant neoplasm of ovary; Mediating; Molecular; Monoclonal Antibodies; Ovarian Tissue; Paclitaxel; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Phase I Clinical Trials; Physiologic Neovascularization; Plasma; Recurrence; Regulation; Reporting; Resistance; Role; Safety; Serous; Signal Pathway; Signal Transduction; Source; T-Lymphocyte; TWIST1 gene; Testing; The Cancer Genome Atlas; Therapeutic; Tissues; Tumor Angiogenesis; Tumor Burden; University of Texas M D Anderson Cancer Center; Vascular Endothelial Growth Factors; Work; angiogenesis; antiangiogenesis therapy; antitumor effect; bevacizumab; cancer cell; cancer therapy; chemotherapy; differential expression; exhaustion; first-in-human; humanized antibody; improved; in vivo; innovation; insight; lead candidate; mortality; mouse model; novel; ovarian neoplasm; phase 1 study; pre-clinical; recruit; response; single cell analysis; targeted treatment; taxane; therapy outcome; tumor; tumor growth; tumor microenvironment; tumorigenesis; wound healing

Project 3 SUMMARY/ABSTRACT High-grade serous ovarian cancer (HGSC) is the most common and aggressive type of epithelial ovarian cancer, and the mortality rates remain unacceptably high. It is well documented that aberrant angiogenesis occurs in the tumor microenvironment (TME) and angiogenesis inhibitors are important for cancer therapy. However, the clinical benefit of bevacizumab (vascular endothelial growth factor (VEGF) targeted antibody) has been limited due to rapid emergence of resistance in most patients with ovarian cancer. Moreover, therapies targeting the VEGF signaling pathway can also result in adverse events and interfere with wound healing since VEGF is known to be also important for physiological angiogenesis. Thus, new targets and approaches aimed at the TME for improving therapeutic outcomes are needed. We identified epidermal growth factor (EGF)-like domain multiple 6 (EGFL6) as the most differentially expressed gene in tumor endothelial cells compared to endothelial cells from normal ovarian tissues and healing wounds. Our preliminary data suggest that high EGFL6 expression in tumors is associated with an immune suppressive TME with high M2 macrophage infiltration. To develop a therapeutic approach for blocking EGFL6, we developed and tested a large number of candidate antibodies; the final candidates have been humanized. Our in vivo results indicated that these antibodies had robust anti-tumor effects and reduced angiogenesis in ovarian cancer models. Based on our compelling preliminary data, we hypothesize that EGFL6 promotes aberrant angiogenesis, and immune suppression, resulting in ovarian cancer growth and progression. Blocking EGFL6 with a monoclonal antibody provides a novel and effective approach for treatment of ovarian cancer. We will test our hypothesis under three Aims: 1) To delineate the molecular regulation of EGFL6 and identify sources of EGFL6 in the tumor microenvironment; 2) To investigate the biological effects of anti-EGFL6 monoclonal antibody as monotherapy or in combination with chemotherapy, anti- VEGF antibody, or immune checkpoint inhibitor; and 3) To determine the safety and tolerability of an anti-EGFL6 antibody in a first-in-human, first-in-class phase I clinical trial in patients with recurrent ovarian cancer. Collectively, the work proposed in this project will provide scientific rationale for developing new anti-EGFL6 based therapies. The proposed studies will provide fundamental mechanistic insights into the role of EGFL6 in regulating immune responses in the TME. Findings from this proposal could significantly impact the clinical outcomes of patients with ovarian cancer.

项目3摘要/摘要 高级浆液卵巢癌（HGSC）是上皮卵巢癌的最常见和侵略性类型， 并且死亡率仍然不可接受。有充分的文献证明，异常血管生成发生在 肿瘤微环境（TME）和血管生成抑制剂对于癌症治疗很重要。但是， 贝伐单抗（血管内皮生长因子（VEGF）靶向抗体）的临床益处受到限制 由于大多数卵巢癌患者的耐药性快速出现。此外，针对的疗法 VEGF信号通路也可能导致不良事件，并干扰伤口愈合，因为VEGF为 已知对于生理血管生成也很重要。因此，针对TME的新目标和方法 需要改善治疗结果。我们确定了表皮生长因子（EGF）样域 与内皮相比，多个6（EGFL6）是肿瘤内皮细胞中最差异表达的基因 来自正常卵巢组织和愈合伤口的细胞。我们的初步数据表明高EGFL6表达 在肿瘤中，与具有高M2巨噬细胞浸润的免疫抑制性TME有关。开发一个 阻止EGFL6的治疗方法，我们开发并测试了大量候选抗体。这 最终候选人已被人性化。我们的体内结果表明这些抗体具有强大的抗肿瘤 卵巢癌模型中的作用和血管生成减少。根据我们引人入胜的初步数据，我们 假设EGFL6促进异常血管生成和免疫抑制，导致卵巢癌 生长和发展。用单克隆抗体阻止EGFL6提供了一种新颖有效的方法 用于治疗卵巢癌。我们将在三个目的下测试我们的假设：1）描绘分子 EGFL6的调节并确定肿瘤微环境中EGFL6的来源； 2）调查 抗EGFL6单克隆抗体作为单一疗法或与化学疗法相结合的生物学作用 VEGF抗体或免疫检查点抑制剂； 3）确定抗EGFL6的安全性和耐受性 复发性卵巢癌患者的第一阶段I期临床试验中的抗体。 总的来说，该项目提出的工作将为开发新的反EGFL 6提供科学原理。 基于疗法。拟议的研究将为EGFL6在 调节TME中的免疫反应。该提案的发现可能会严重影响临床 卵巢癌患者的结局。